Copper- or phosphine-catalyzed reaction of alkynes with isocyanides. Regioselective synthesis of substituted pyrroles controlled by the catalyst

Article abstract of DOI:10.1021/ja051875m

The copper-catalyzed reaction of isocyanides (CNCH₂EWG ¹) 1 with electron-deficient alkynes (RC=CEWG²) 2 gave the 2,4-di-EWG-substituted pyrroles 3 selectively, whereas the phosphine-catalyzed reaction of 1 with 2 afforded

Full text of DOI:10.1021/ja051875m

Published on Web 06/03/2005
Copper- or Phosphine-Catalyzed Reaction of Alkynes with
Isocyanides. Regioselective Synthesis of Substituted Pyrroles
Controlled by the Catalyst
Shin Kamijo, Chikashi Kanazawa, and Yoshinori Yamamoto*
Contribution from the Department of Chemistry, Graduate School of Science, Tohoku UniVersity,
Sendai 980-8578, Japan
Received March 24, 2005; E-mail: yoshi@yamamoto1.chem.tohoku.ac.jp
Abstract: The copper-catalyzed reaction of isocyanides (CNCH2EWG1) 1 with electron-deficient alkynes
(RC≡CEWG2) 2 gave the 2,4-di-EWG-substituted pyrroles 3 selectively, whereas the phosphine-catalyzed
reaction of 1 with 2 afforded the 2,3-di-EWG-subsituted pyrroles 4. Accordingly, regioselective synthesis
of substituted pyrroles has been achieved by merely choosing the catalyst.
compound to form carbocycles (hydrocarbonation).7 Those
Introduction
direct additions are initiated with activation of a C-H bond in
Carbon-carbon bond formation is one of the most important
and fundamental reactions in synthetic organic chemistry. Recent
demands for development of environmentally benign processes
have led many researchers to the study of eco-chemical
transformations. One of the directions of researches to fulfil
those requirements is an exploration of atom-economical
processes,1 in which all the atoms in substrates are taken into
products. In such processes, no harmful and useless wastes are
generated along with production of desired compounds. We
envisioned that catalytic direct addition2 and cycloaddition3 of
carbon pronucleophiles to a carbon-carbon unsaturated bond
would bring about highly atom-economical processes as shown
in Scheme 1. The ruthenium-catalyzed direct addition of
activated methylenes and methines to activated alkynes (Michael
reaction)4 and the palladium-catalyzed direct addition of acti-
vated methylenes and methines to nonactivated allenes5 give
the corresponding C-C bond forming products in high yields
in atom-economical manner. During the course of investigations
on the palladium-catalyzed direct addition of carbon pronu-
cleophiles to nonactivated C-C unsaturated bonds,6 we found
a cyclization of acetylenes tethered with an active methine
pronucleophiles by a metal catalyst, and subsequent insertion
of the C-C triple bond into the metal-hydrogen (or metal-
carbon) bond accounts for the formation of products. The
dimerization of conjugated enynes in the presence of a palladium
catalyst gives the 2,6-disubstituted styrenes regioselectively
(benzannulation).8
In the previous reactions shown in Scheme 1, the ordinary
carbon pronucleophiles, HCR3(EWG)2, were used as the partner
of alkynes (or alkenes). It occurred to us that the use of
isocyanides, instead of the ordinary pronucleophiles, would bring
about a different type of atom-economical process. The reaction
of the metalated (or nonmetalated) isocyanides with carbon-
carbon and carbon-heteroatom unsaturated bonds is summarized
in Scheme 2. The reaction of the two substrates, the nucleophiles
and electrophiles, produces the C-C bond forming intermediate
I which gives the heterocycles (shown in Scheme 2) through
further transformations. To the best of our knowledge, the
transition metal-catalyzed reaction of isocyanides is rather
limited so far, but the application of isocyanides to various
transformations has been rapidly expanding these days.9,10
We herein report that the copper-catalyzed reaction of
isocyanides 1 with activated alkynes 2 produces the 2,4-di-
EWG-substituted pyrroles 3 in good yields, whereas the
phosphine-catalyzed reaction of 1 with 2 affords the 2,3-di-
EWG-substituted pyrroles 4 regioselectively (Scheme 3).11 This
interesting regioreversal of the heteroaromatization stems from
the regiodifferentiated addition of the nucleophilic isocyanide
to 2, which is controlled by the catalyst species; the ordinary
Michael addition of the metalated isocyanide to the â-carbon
(1) (a) Trost, B. M. Science 1991, 254, 1471-1477. (b) Trost, B. M. Angew
Chem., Int. Ed. Engl. 1995, 34, 259-281.
(2) Perlmutter, P. Conjugated Addition Reactions in Organic Synthesis;
Pergamon: Oxford, 1992.
(3) Carruthers, W. Cycloaddition Reactions in Organic Synthesis; Pergamon:
Oxford, 1990.
(4) (a) Naota, T.; Taki, H.; Mizuno, M.; Murahashi, S.-I. J. Am. Chem. Soc.
1989, 111, 5954-5955. Reviews, see: (b) Murahashi, S.-I.; Naota, T. Bull.
Chem. Soc. Jpn. 1996, 69, 1805-1824. (c) Murahashi, S.-I.; Takaya, H.
Acc. Chem. Res. 2000, 33, 225-233.
(5) (a) Yamamoto, Y.; Al-Masum, M.; Asao, N. J. Am. Chem. Soc. 1994, 116,
6019-6020. (b) Patil, N. T.; Pahadi, N. K.; Yamamoto, Y. Synthesis 2004,
13, 2186-2190.
(6) For a review on the palladium-catalyzed pronucleophile addition to
unactivated carbon-carbon multiple bonds, see (a) Yamamoto, Y.;
Radhakrishnan, U. Chem. Soc. ReV. 1999, 28, 199-207 and references
therein. For palladium-catalyzed direct allylations of carbon-pronucleophiles
via hydrocarbonation of alkynes, see: (b) Kadota, I.; Shibuya, A.; Gyoung,
Y. S.; Yamamoto, Y. J. Am. Chem. Soc. 1998, 120, 10262-10263. (c)
Patil, N. T.; Kadota, I.; Shibuya, A.; Gyoung, Y. S.; Yamamoto, Y. AdV.
Synth. Catal. 2004, 346, 800-804.
(7) Tsukada, N.; Yamamoto, Y. Angew. Chem., Int. Ed. Engl. 1997, 36, 2477-
2480.
(8) (a) Saito, S.; Salter, M. M.; Gevorgyan, V.; Tsuboya, N.; Tando, K.;
Yamamoto, Y. J. Am. Chem. Soc. 1996, 118, 3970-3971. Reviews on the
palladium-catalyzed benzannulation, see: (b) Gevorgyan, V.; Yamamoto,
Y. J. Organomet. Chem. 1999, 576, 232-247 and references therein. (c)
Saito, S.; Yamamoto, Y. Chem. ReV. 2000, 100, 2901-2915 and references
therein.
9
9260
J. AM. CHEM. SOC. 2005, 127, 9260-9266
10.1021/ja051875m CCC: $30.25 © 2005 American Chemical Society

Regioselective Synthesis of Substituted Pyrroles
A R T I C L E S
Scheme 1
Scheme 2
Scheme 3
Results and Discussion
of 2 (path a) gives 3, while the addition of the nucleophilic iso-
cyanide to the R-carbon attached to EWG2 affords 4 (path b).
Copper-Catalyzed Addition Leading to the Formation of
2,4-Di-EWG-Substituted Pyrroles. Pyrroles are one of the
important classes of heterocyclic compounds and found broad
use in both synthetic organic chemistry and material science.12
Pyrroles are often seen as a building block in naturally occurring
and biologically active compounds such as chlorophylls and
haems. Polypyrroles are known to exhibit conductivity, which
can be applied as electric devices. Due to their characteristic
(9) For activation of a C-H bond of isocyanides using a transition metal
catalyst, see: (a) Saegusa, T.; Ito, Y.; Kinoshita, H.; Tomita, S. J. Org.
Chem. 1971, 36, 3316-3323 [Cu]. (b) Takaya, H.; Kojima, S.; Murahashi,
S. Org. Lett. 2001, 3, 421-424 [Rh]. (c) Motoyama, Y.; Kawakami, H.;
Shimozono, K.; Aoki, K.; Nishiyama, H. Organometallic 2002, 21, 3408-
3416 [Pt, Rh]. (d) Ito, Y.; Sawamura, M.; Hayashi, T. J. Am. Chem. Soc.
1986, 108, 6405-6406 [Au]. (e) Tongi, A.; Pastor, S. D. J. Org. Chem.
1990, 55, 1649-1664 [Au]. (f) Sawamura, M.; Hamashima, H.; Ito, Y. J.
Org. Chem. 1990, 55, 5935-5936 [Ag]. (g)Hayashi, T.; Kishi, E.;
Soloshonok, V. A.; Uozumi, Y. Tetrahedron Lett. 1996, 37, 4969-4972
[Au].
(10) Base promoted reactions of isocyanides (noncatalytic reactions): (a) Gerhart,
F.; Scho¨llkopf, U. Tetrahedron Lett. 1968, 59, 6231-6234. (b) van Leusen,
A. M.; Wildeman, J.; Oldenziel, O. H. J. Org. Chem. 1977, 42, 1153-
1159. (c) van Leusen, A. M.; Siderius, H.; Hoogenboom, B. E.; van Leusen,
D. Tetrahedron Lett. 1972, 52, 5337-5340. (d) Barton, D. H. R.; Zard, S.
Z. J. Chem. Soc., Chem. Commun. 1985, 1098-1100. (e) Saikachi, H.;
Kitagawa, T.; Sasaki, H. Chem. Pharm. Bull. 1979, 27, 2857-2861. (f)
Murakami, T.; Otsuka, M.; Ohno, M. Tetrahedron Lett. 1982, 45, 4729-
4732.
(12) For reviews on the chemistry of pyrroles, see: (a) In ComprehensiVe
Heterocyclic Chemistry; Katritzky, A. R., Rees, C. W., Eds.; Pergamon:
Oxford, 1984; Vol. 4. (b) Jackson, A. H. In CopprehensiVe Organic
Chemistry; Barton, D., Ollis, W. D., Eds.; Pergamon: Oxford, 1979; Vol.
4, pp 275-320. (c) Black, D. S. In Science of Synthesis; Maas, G., Ed.;
Georg Thieme Verlag: Stuttgart, 2001; Vol. 9, pp 441-552. (d) Gossauer,
A. In Methoden der Organischen Chemie (Houben-Weyl); Kreher, R. P.,
Ed.; Georg Thieme Verlag: Stuttgart, 1994; E6a, pp 556-798. (e) Joule,
J. A.; Mills, K. In Heterocyclic Chemistry; Blackwell Science: Oxford,
2000; Chapter 13.
(11) For a preliminary communication, see: Kamijo, S.; Kanazawa, C.;
Yamamoto, Y. Tetrahedron Lett. 2005, 46, 2563-2566.
9
J. AM. CHEM. SOC. VOL. 127, NO. 25, 2005 9261

A R T I C L E S
Kamijo et al.
Table 1. Effects of the Metal Catalysts in the Reaction of 1a and
properties, extensive investigations have been made to elucidate
reactivity of pyrrole rings and to develop preparative methods
of pyrrole structures.
2aa
NMR yield
entry
catalyst
ligand
of 3ab, %
Many excellent methodologies have been developed for
constructing pyrrole rings.12,13 One of the major strategies for
synthesis of pyrroles is dehydrative coupling between ketones
and amines. For instance, a condensation of 1,4-diketones with
amines is known as the Paal-Knorr synthesis, a combination
of R-amino ketones and â-dicarbonyl compounds is known as
the Knorr synthesis, and a condensation of R-haloketones with
â-keto ester in the presence of amines is known as the Hantzsh
synthesis. The cycloaddition between activated olefins (Michael
acceptors) and isocyanides under basic conditions is also a
representative method for synthesis of pyrroles. The reaction
of nitroalkenes with isocyanoacetates is known as the Barton-
Zard synthesis, and the reaction of Michael acceptors and
TosMIC (tosylmethyl isocyanide)14 is called the van Leusen
synthesis. These cycloadditions produce desired pyrroles,
although they always come with elimination of nitrous acid and
toluenesulfinate, respectively.
During the course of research on the cyanamide15 and the
triazole16 synthesis via the three-component coupling reactions
of allyl carbonate, TMSN3, and isocyanides (or alkynes), we
discovered that a combination of copper and phosphine catalysts
promoted a reaction between ethyl isocyanoacetate 1a and ethyl
2-butynoate 2a to produce some cyclized products. A precise
analysis of the spectroscopic data revealed that the reaction using
Cu2O and PPh3 catalysts gave a mixture of 2,4-di(ethoxycar-
bonyl)-3-methylpyrrole 3a (R ) Me, EWG1 ) EWG2 ) CO2-
Et in eq 1) and 2,3-di(ethoxycarbonyl)-4-methylpyrrole 4a (R
1
2
3
4
5
6
7
8
9
10
11
12
13
14
Cu2O
PPh3
Pr3N
35c
50
49
46
22
42
66
48
48
trace
33
33
26
41
Cu2O
Cu2O
Cu2O
Cu2O
Cu2O
Cu2O
Cu2O
Cu2O
CuCle
Cu(OMe)2
N-methylmorpholine
pyridine
DBU
TEEDAd
phend
bipyd
none
phend
e
phend
Cu powdere
HRh(PPh3)4
H2Ru(PPh3)4
phend
none
none
a Unless otherwise noted, the reaction of 1a (0.5 mmol; EWG1 ) CO2Et
in eq 1) and 2a (0.7 mmol; R ) Me, EWG2 ) CO2Et in eq 1) was conducted
in dioxane (1 mL) in the presence of catalyst (25 µmol, 5 mol %) and
ligand (100 µmol, 20 mol %) at 100 °C for 6 h. b NMR yield using p-xylene
as an internal standard. c 4a (R ) Me, EWG1 ) EWG2 ) CO2Et in eq 1)
was obtained in 12% NMR yield. d 10 mol % of the ligand was used. e 10
mol % of the catalyst was used.
yields (entries 2-4). The employment of DBU (1,8-diazabicyclo-
[5.3.0]undec-7-ene) decreased the yield of 3a (entry 5). The
diamines, such as TEEDA (N,N,N′,N′-tetraethylethylenedi-
amine), phen (1,10-phenanthroline), and bipy (2,2′-dipyridyl),
also catalyzed the pyrrole-forming reaction (entries 6-8).
Among them, the combination of Cu2O and phen showed the
highest catalytic activity for regioselective formation of 3a. The
formation of 3a took place by merely using Cu2O salt, but the
yield was slightly lower compared with the yield obtained
through the reaction using the Cu2O and phen catalyst system
(entry 9). We also investigated the reactivity of some other
copper catalysts, such as CuCl, Cu(OMe)2, and Cu powder, but
the yields of 3a were low (entries 10-12). The rhodium9b and
ruthenium4a complexes promoted the pyrrole formation to some
extent (entries 13 and 14). Among the solvents we tested, 1,4-
dioxane showed the best result for formation of the pyrrole 3a.
Solvents such as toluene and ethyl acetate produced the desired
product 3a in moderate yields, whereas polar solvents, such as
DMF, CH3CN, and 1,2-dichloroethane, resulted in low yields.
When the reaction was carried out at lower temperature (80
°C), a significant decrease of the yield was observed and a
prolonged reaction time was required.
Since the optimal reaction conditions were in hand for the
copper-catalyzed heteroaromatization, the reaction of ethyl
isocyanoacetate 1a with various electron-deficient alkynes 2 was
carried out and the results are summarized in Table 2. The
reaction of ethyl 2-butynoate 2a with 1a was conducted with
Cu2O (5 mol %) and phen (10 mol %) in dioxane at 100 °C.
The substrate 1a was consumed in 2 h, and 2,4-di(ethoxycar-
bonyl)-3-methylpyrrole 3a was obtained in 64% isolated yield
(entry 1). It was possible to use the alkynol 2b directly without
protecting a hydroxyl group, and the corresponding product 3b
was formed in good yield (entry 2). The substrate 2c attached
with a cyclohexyl group produced the pyrrole 3c in high yield
(entry 3); however the bulky tert-butyl substituted alkyne 2d
afforded the corresponding product 3d in only 15% yield (entry
4). The steric congestion around the triple bond seems to
diminish the yield of the heteroaromatization reaction. Both ethyl
phenylpropiolate 2e and ethylpropiolate 2f reacted in a similar
) Me, EWG1 ) EWG2 ) CO2Et in eq 1) as shown in entry 1
in Table 1. Detailed survey on combination between catalysts
and ligands disclosed that Cu2O and a nitrogen ligand effectively
promoted the regioselective formation of the 2,4-di-EWG-
substituted pyrrole 3a. Both alkyl and aromatic amines, such
as Pr3N, N-methylmorpholine, and pyridine, worked as a
pertinent ligand to afford the expected pyrrole 3a in moderate
(13) For recent representative examples on the pyrrole synthesis, see: (a) Balme,
G. Angew. Chem., Int. Ed. 2004, 43, 6238-6241 and references therein.
(b) Siriwardane, A. I.; Kathriarachchi, K. K. A. D. S.; Nakamura, I.;
Gridnev, I. D.; Yamamoto, Y. J. Am. Chem. Soc. 2005, 126, 13898-13899.
(c) Ramanathan, B.; Keith, A. J.; Armstrong, D.; Odom, A. L. Org. Lett.
2004, 6, 2957-2960. (d) Gabriele, B.; Salerno, G.; Fazio, A. J. Org. Chem.
2003, 68, 7853-7861. (e) Kel’in, A. V.; Sromek, A. W.; Gevorgyan, V. J.
Am. Chem. Soc. 2001, 123, 2074-2075. (f) Reference 9b. (g) Ooi, T.;
Ohmatsu, K.; Ishii, H.; Saito, A.; Maruoka, K. Tetrahedron Lett. 2004, 45,
9315-9317.
(14) Leusen, D. v.; Leusen, A. M. v. Org. React. 2001, 57, 417-666 and
references therein.
(15) Kamijo, S.; Jin, T.; Yamamoto, Y. Angew. Chem., Int. Ed. 2002, 41, 1780-
1782.
(16) (a) Kamijo, S.; Jin, T.; Huo, Z.; Yamamoto, Y. J. Am. Chem. Soc. 2003,
125, 7786-7787. (b) Kamijo, S.; Jin, T.; Huo, Z.; Yamamoto, Y. J. Org.
Chem. 2004, 69, 2386-2393. (c) Kamijo, S.; Jin, T.; Yamamoto, Y.
Tetrahedron Lett. 2004, 45, 689-691.
9
9262 J. AM. CHEM. SOC. VOL. 127, NO. 25, 2005

Regioselective Synthesis of Substituted Pyrroles
A R T I C L E S
Table 2. Copper-Catalyzed Pyrrole Synthesis Using Various
Alkynes 2 and 1aa
of the isocyanide does not interfere with the progress of the
present heteroaromatization. The reactions of the amide 1d and
the phosphonate 1e gave the expected pyrroles 3o and 3p in
good to high yields (entries 3 and 4). Surprisingly, benzyl
isocyanide 2f gave the corresponding pyrrole 3q in 46% yield
under the standard reaction conditions (entry 5).
entry
R
EWG2
2
time, h
3
yield, %
1
2
3
4
5
6
7
8
9
Me
HO(CH2)4
cyclo-C6H11
t-Bu
Ph
H
CO2Et
Ph
Ph
Ph
CO2Et
CO2Et
CO2Et
CO2Et
CO2Et
CO2Et
CO2Et
COMe
CONEt2
CN
2a
2b
2c
2d
2e
2f
2g
2h
2i
2
1
2
3
2
1
4.5
1
1
3a
3b
3c
3d
3e
3f
3g
3h
3i
64
65
73
15 (26)b
79
A plausible mechanism for the copper-catalyzed heteroaro-
matization between isocyanides 1 and electron-deficient alkynes
2 is illustrated in Scheme 4. The reaction starts with activation
of a C-H bond of the isocyanides 1 by the influence of Cu2O
catalyst. The R-cuprioisocyanide A or its tautomer A′ is formed
by the reaction between 1 and Cu2O through the extrusion of
H2O.18 Then, the 1,4-addition of the nucleophilic intermediate
A and/or A′ to the alkynes 2, activated by an electron-
withdrawing groups, takes place. The newly generated copper-
enolate would intramolecularly attack the isonitrile carbon to
generate the cyclized intermediate B; this is a formal [3 + 2]
cycloaddition process. The C-Cu bond in the intermediate B
is protonated by isocyanides 1, and the intermediate C is
produced with regeneration of the copper-intermediate A and/
or A′. The continuous formation of this active species A and/or
A′ makes the catalytic cycle operative. 1,5-Hydrogen shift in
the intermediate C forms the 2,4-di-EWG-substituted pyrroles
3 as the sole product.
73
43
22c
11
10
11
2j
2k
1
1
3j
3k
22
13
Ph
SO2Ph
a Unless otherwise noted, the reaction between 1a (0.5 mmol; EWG1 )
CO2Et in eq 1) and 2 (0.6 mmol) was conducted in dioxane (1 mL) in the
presence of Cu2O (25 µmol, 5 mol %) and 1,10-phenanthroline (50 µmol,
10 mol %) at 100 °C for the time indicated in Table 2. b The yield increased
to 26% when 10 mol % Cu2O and 20 mo % phen were used. c The oxazoline
was obtained in 14% yield.17
Table 3. Copper-Catalyzed Pyrrole Synthesis Using Various
Isocyanides 1 and 2aa
entry
EWG1
1
time, h
3
yield, %
1
2
3
4
5
CO2Me
CO2 tBu
CONEt2
P(O)(OEt)2
Ph
1b
1c
1d
1e
1f
2
3.5
4
24
6
3m
3n
3o
3p
3q
54
71
75
59
46
We carried out the heteroaromatization between the deuterated
isocyanide 1a-d9e and the alkyne 2e in the presence of the
copper catalyst (eq 3). As expected, the reaction gave the pyrrole
3e-d in 69% yield with 70% content of the deuterium on the
pyrrole ring.
a The reaction between 1 (0.5 mmol) and 2a (0.6 mmol; R ) Me, EWG2
) CO2Et in eq 1) was conducted in dioxane (1 mL) in the presence of
Cu2O (25 µmol, 5 mol %) and 1,10-phenanthroline (50 µmol, 10 mol %)
at 100 °C for the time indicated in Table 3.
way to form the pyrroles 3e and 3f in high yields, respectively
(entries 5 and 6). Highly electron-deficient acetylenedicarboxy-
late 2g produced the expected pyrrole 3g in 44% yield (entry
7). The reactions of the alkynes 2h-2k activated with various
electron-withdrawing groups, such as keto, amido, cyano, and
sulfonyl group, gave the corresponding pyrroles 3h-3k in low
yields (entries 8-11). The diyne 2l produced the corresponding
product 3l containing two pyrrole rings in 77% yield (eq 2).
Phosphine-Catalyzed Addtion Leading to the Formation
of 2,3-Di-EWG-Substituted Pyrroles.11 One of the significant
advances in the field of synthetic organic chemistry in recent
years is development of new catalytic reactions using simple
organic molecules, called organocatalysis.19 Various types of
organic molecules have already been revealed to behave as an
organocatalyst, and numerous efforts have been made to design
more reactive catalysts. Phosphine phosphorus is one of the
(17) (a) Reference 9a. (b) Saegusa, T.; Murase, I.; Ito, Y. Bull. Chem. Soc. Jpn.
1972, 45, 830-833. (c) Ito, Y.; Matsuura, T.; Saegusa, T. Tetrahedron
Lett. 1985, 26, 5781-5784.
(18) For Cu2O-catalyzed activation of a C-H bond in isocyanides with extrusion
of H2O, see: (a) Reference 17. (b) Ito, Y.; Konoike, T.; Saegusa, T. J.
Organomet. Chem. 1975, 85, 395-401. (c) Ito, Y.; Kobayashi, K.; Saegusa,
T. J. Org. Chem. 1979, 44, 2030-2032. The reactions between copper
catalysts and isocyanides have been well studied by Professors Ito and
Saegusa; however, we cannot completely exclude the possibility that H-Cu
species might act as an active catalyst similar to the case of the Rh-catalyzed
reaction of isocyanides in ref 9b. We thank a reviewer for pointing this
out.
We next conducted the pyrrole forming reaction employing
ethyl 2-butynoate 2a and a variety of isocyanides 1 (Table 3).
The isocyanides having methoxycarbonyl 1b and tert-butoxy-
carbonyl group 1c afforded the corresponding pyrroles 3m and
3n in 54% and 71% yields (entries 1 and 2). It is clear that
installation of sterically bulky tert-butyl group in an ester moiety
9
J. AM. CHEM. SOC. VOL. 127, NO. 25, 2005 9263

A R T I C L E S
Kamijo et al.
Scheme 4. A Proposed Mechanism for the Copper-Catalyzed Reaction
Table 4. Effects of Phosphines in the CuCl-Catalyzed Reaction
between 1a and 2aa
cycloaddition between electron-deficient alkynes 2 and isocya-
nides 1 under a phosphine catalyst is not known so far.24
During optimization on the copper-catalyzed addition of 1a
to 2a, we encountered that the use of CuCl and PPh3 catalyst
produced the 2,3-di-EWG-substituted pyrrole together with trace
amounts of the 2,4-di-EWG-substituted one (eq 4; see also entry
1, Table 1). The effects of phosphine additives on the yield of
entry
phosphine
NMR yield of 4a, %b
1c
2
3
4
5
PPh3
50
38
0
0
0
(p-MeO-C6H4)3P
(p-CF3-C6H4)3P
(2-furyl)3P
P(OPh)3
6
7
8
(o-tolyl)3P
PBu3
(cyclohexyl)3P
dppe
dppp
dppb
0
34
13
50
63
50
25
0
9d
10d
11d
12d
13d
dppf
BINAP
a Unless otherwise noted, the reaction of 2a (0.6 mmol; R ) Me, EWG2
) CO2Et in eq 4) and 1a (0.5 mmol; EWG1 ) CO2Et in eq 4) was conducted
in dioxane (1 mL) in the presence of CuCl (50 µmol, 10 mol %) and
phosphine (150 µmol, 30 mol %) at 100 °C for 6 h. b NMR yield using
p-xylene as an internal standard. c CuCl(PPh3)3 (50 µmol, 10 mol %) was
used as a catalyst instead of CuCl and PPh3. d Bidentate phosphine (15 mol
%) was used.
4a are summarized in Table 4. Arylphosphines, such as PPh3
and electron-rich tris(p-methoxyphenyl)phosphine, produced the
corresponding pyrrole 4a in moderate yields (entries 1 and 2),
whereas electron-deficient tris(p-trifluoromethylphenyl)phos-
phine, tris(2-furyl)phosphine, and triphenyl phosphite did not
catalyze the reaction at all (entries 3-5). The sterically
congested tri(o-tolyl)phosphine also did not promote the reaction
either (entry 6). Alkylphosphines, such as PBu3 and tricyclo-
hexylphosphine, were less effective than PPh3 (entries 7 and
8). The reactivity of the bidentate phosphines, such as dppe (1,2-
bis(diphenylphosphino)ethane), dppp (1,3-bis(diphenylphos-
phino)propane), and dppb (1,4-bis(diphenylphosphino)butane),
were comparable to that of PPh3 (entries 9-11). Among them,
elements useful for this purpose. It is known that isomerization,20
cyclization,21 and addition reactions22 of electron-deficient
alkynes and allenes are catalyzed by organophosphine cata-
lysts.23 However, pyrrole formation via a formal [3 + 2]
(19) For reviews on organocatalyzed reactions, see: (a) Dalko, P. I.; Moisan,
L. Angew. Chem., Int. Ed. 2001, 40, 3726-3748 and references therein.
(b) Johnson, J. S. Angew. Chem., Int. Ed. 2004, 43, 1326-1328. (c) Shin
Y. Acc. Chem. Res. 2004, 37, 488-496. (d) Ooi, T.; Maruoka, K. Acc.
Chem. Res. 2004, 37, 526-533. (e) List, B. Acc. Chem. Res. 2004, 37,
548-557. (f) Saito, S.; Yamamoto, H. Acc. Chem. Res. 2004, 37, 570-
579. (g) Notz, W.; Tanaka, F.; Darbas, C. F., III. Acc. Chem. Res. 2004,
37, 580-591.
(20) (a) Trost, B, M.; Kazmaier, U. J. Am. Chem. Soc. 1992, 114, 7933-7935.
(b) Guo, C.; Lu, X. J. Chem. Soc., Perkin Trans. 1 1993, 1921-1923.
(21) (a) Zhang, C.; Lu, X. J. Org. Chem. 1995, 60, 2906-2908. (b) Xu, Z.; Lu,
X. J. Org. Chem. 1998, 63, 5031-5041.
(22) (a) Trost, B. M.; Li, C.-J. J. Am. Chem. Soc. 1994, 116, 3167-3168. (b)
Zhang, C.; Li, X. Synlett 1995, 645-646. (c) Alvarez-Ibarra, C.; Csa´ky¨,
A. G.; Olivia, C. G. J. Org. Chem. 2000, 65, 3544-3547.
(23) For reviews on phosphine-mediated and -catalyzed reactions, see: (a) Lu,
X.; Zhang, C.; Xu, Z. Acc. Chem. Res. 2001, 34, 535-544 and reference
therein. (b) Valentine, D. H., Jr.; Hillhouse, J. H. Synthesis 2003, 317-
334 and reference therein.
(24) For phosphine-mediated furan synthesis, see: Jung, C.-K.; Wang, J.-C.;
Krische, M. J. J. Am. Chem. Soc. 2004, 126, 4118-4119.
9
9264 J. AM. CHEM. SOC. VOL. 127, NO. 25, 2005

Regioselective Synthesis of Substituted Pyrroles
A R T I C L E S
Table 5. Phosphine-Catalyzed Pyrrole Synthesis Using Various
Alkynes 2 and 1aa
Table 6. Phosphine-Catalyzed Pyrrole Synthesis Using Various
Isocyanides 2 and 1ea
entry
R
EWG2
2
time, h
4
yield, %
entry
EWG1
1
time, h
4
yield, %
1
2
3
Me
CO2Et
CO2Et
CO2Et
CO2Et
CO2Et
CO2Et
CO2Et
CO2Et
CO2Et
CO2Et
CO2Et
CO2Et
COMe
CONEt2
CN
2a
2m
2b
2c
2c
2d
2e
2n
2o
2p
2f
2
12
2
4a
4b
4c
4d
4d
4e
4f
4g
4h
4i
4j
4k
4l
4m
4n
60
73
59
66
64
1
2
3
4
CO2 tBu
CONEt2
P(O)(OEt)2
SO2(p-Me-C6H4)
1c
1d
1e
1g
2
3.5
24
24
4o
4p
4q
4r
70
CH3(CH2)5
HO(CH2)4
cyclo-C6H11
cyclo-C6H11
t-Bu
27
18b
20b
4
24
19
24
1.5
3.5
0.75
4
0.5
0.5
1
5b
6
c
a The reaction between 1e (0.5 mmol; R ) Ph, EWG2 ) CO2Et in eq 4)
and 2 (0.6 mmol) was conducted in dioxane (1 mL) in the presence of
dppp (75 µmol, 15 mol %) at 100 °C for the time indicated in Table 6.b A
small amount of the starting alkyne 2e was recovered.
-
7
8
9
10
11
12
13
14
15
Ph
79
79
48
19
p-MeO-C6H4
p-CF3-C6H4
isopropenyl
H
CO2Et
Ph
d
-
introduction of an electron-donating group on the aromatic ring
slightly retarded the consumption of the substrate, though the
product 4g was obtained in high yield (entry 8). On the contrary,
the introduction of an electron-withdrawing group shortened the
reaction time but the yield of 4h remained moderate (entry 9).
The reaction of the conjugated enyne 2p took place chemose-
lectively at the alkyne moiety and produced the corresponding
pyrrole 4i, although the yield was modest (entry 10). The
reaction of the terminal acetylene 2f and the highly electron-
deficient acetylenedicarboxylate 2g gave a complex mixture of
unidentified products, probably due to the polymerization of
acetylenes (entries 11 and 12). It is worthy to mention that the
acetylenes bearing keto 2h, amido 2i, and cyano group 2j served
as a starting material to afford the corresponding pyrroles 4l-
4n, respectively (entries 13-15).
We next examined the phosphine-catalyzed heteroaromati-
zation between ethyl phenylpropiolate 2e and the various
isocyanides 1c-1d, and 1g (Table 6). Installation of the bulky
tert-butyl group in the ester moiety, as in 1c, did not affect the
reaction progress, and the corresponding pyrrole 4o was
produced in 70% yield (entry 1). The isocyanides having amido
1d and phosphonate 1e and sulfonyl group 1g afforded the
corresponding pyrroles 4p, 4q, and 4r, respectively, however
the yields were rather low (entries 2-4). Benzyl isocyanide 1f
did not give the desired pyrrole under the present conditions,
and recovery of the starting materials was observed.
A plausible mechanism for the phosphine-catalyzed het-
eroaromatization is depicted in Scheme 5. The reaction is most
probably initiated by 1,4-addition of the nucleophilic phosphine
to the activated alkynes 2 to form the zwitterionic intermediate
D.27 This step induces umpolung of reactivity of the activated
alkyne 2. The abstraction of an acidic proton in the isocyanide
1 gives the cationic intermediate E and the carbanion 1′.28 The
carbanion would attack the carbon bearing EWG2 of E,29 and
the newly formed anionic center would attack the isocyanide
carbon of 1′ to form the cyclic intermediate F; this is a formal
[3 + 2] cycloaddition process. Intramolecular proton migration
and elimination of the phosphine catalyst produce the intermedi-
ate G. Subsequent 1,5-hydrogen shift furnishes the pyrrole 4
as a product.
d
2g
2h
2i
-
77
Ph
Ph
24
0.5
17e
35
2j
a Unless otherwise noted, the reaction between 2 (0.5 mmol) and 1a (0.6
mmol; EWG1 ) CO2Et in eq 4) was conducted in dioxane (1 mL) in the
presence of dppp (75 µmol, 15 mol %) at 100 °C for the time indicated in
Table 5. b CuCl (25 µmol, 5 mol %) was added. c A significant amount of
the alkyne 2d and the isocyanide 1a was recovered. d Complex mixture.
e The starting alkyne 2i was recovered in 67% yield.
dppp25 gave the highest yield of the desired pyrrole 4a. The
employment of dppf (1,1′-bis(diphenylphosphino)ferrocene) and
BINAP (2,2′-bis(diphenylphosphino)-1,1′-binaphthyl) did not
improve the yield of 4a. Very interestingly, further studies
disclosed that the present heteroaromatization could be catalyzed
merely by a phosphine, dppp, without the aid of CuCl. The
reaction took place in a wide variety of solvents, such as toluene,
1,2-dichloroethane, 1,4-dioxane, ethyl acetate, and CH3CN.
Among them, dioxane gave the highest yield of 4a. The reaction
proceeded at lower temperature (80 °C); however, a longer
reaction time was required.
We carried out the phosphine-catalyzed heteroaromatization
of various electron-deficient alkynes 2 with ethyl isocyanoac-
etate 1a under the optimal conditions; dppp (15 mol %) in
dioxane at 100 °C, and the results are summarized in Table 5.
The reaction between 2a and 1a was completed in 2 h to give
2,3-di(ethoxycarbonyl)-4-methylpyrrole 4a in 60% isolated yield
(entry 1). The alkyne 2m bearing hexyl group afforded the
pyrrole 4b in 73% yield (entry 2). Even the unprotected alkynyl
alcohol 2b could be used directly as a starting material and the
corresponding product 4c was obtained in 59% yield (entry 3).
The reaction of the alkyne 2c attached with a cyclohexyl group
proceeded smoothly to produce the desired product 4d in 66%
yield after 24 h (entry 4). When the same reaction was carried
out in the presence of a catalytic amount of CuCl, the reaction
time was reduced without affecting the yield of 4d (entry 5).26
In the case of the alkyne 2d bearing a bulky tert-butyl group,
no reaction took place even after 24 h and a significant amount
of the starting materials was recovered (entry 6). The reactions
of aromatic acetylenes 2e, 2n, and 2o gave the corresponding
pyrroles 4f, 4g, and 4h, respectively (entries 7-9). The
(27) (a) Reference 23. (b) Grossman, R. B.; Comesse, S.; Rasne, R. M.; Hattori,
K.; Delong, M. J. Org. Chem. 2003, 68, 871-874. (c) Inanaga, J.; Baba,
Y.; Hanamoto, T. Chem. Lett. 1993, 241-244. (d) Wang, J.-C.; Ng, S.-S.;
Krische, M. J. J. Am. Chem. Soc. 2003, 125, 3682-3683.
(28) The pKa value of isocyanides is slightly larger than those of the
corresponding cyanides; see: (a) Castejon, H.; Wiberg, K. B. J. Org. Chem.
1998, 63, 3937-3942. (b) Bordwell, F. G.; Branca, J. C.; Bares, J. E.;
Filler, R. J. Org. Chem. 1988, 53, 780-782 [pKa of methyl cyanoacetate
) 12.8].
(29) Similar types of inverse 1,4-addition reactions have been reported; see:
(a) Hane´danian, M.; Loreau, O.; Taran, F.; Mioskowski, C. Tetrahedron
Lett. 2004, 45, 7035-7038. (b) Lu, C.; Lu, X. Org. Lett. 2002, 4, 4677-
4679.
(25) The reactions using dppp as a catalyst: (a) Trost, B. M.; Li, C.-J. J. Am.
Chem. Soc. 1994, 116, 10819-10820. (b) Trost, B. M.; Dake, G. R. J.
Org. Chem. 1997, 62, 5670-5671. (c) Trost, B. M.; Dake, G. R. J. Am.
Chem. Soc. 1997, 119, 7579-7596.
(26) The copper effect might be explained as follows, although it is speculative.
CuCl catalyst coordinates both dppp and the isocyanide. This complexation
makes it easy to generate the anionic species 1′ in Scheme 5 and stabilizes
the derived intermediate as a copper-enolate. Moreover, the ligation between
the phosphine in E and the copper-enolate of 1′ accelerates the formation
of the cyclized intermediate F. The combination of CuCl and isocyanides
has been studied in ref 17c.
9
J. AM. CHEM. SOC. VOL. 127, NO. 25, 2005 9265

A R T I C L E S
Kamijo et al.
Scheme 5. A Proposed Mechanism for the Phosphine-Catalyzed Reaction
an Ar atmosphere. The solution was stirred at 100 °C for 2 h. After
the consumption of 1a, the reaction mixture was cooled to room
temperature and filtered through a short Florisil pad and concentrated.
The residue was purified by column chromatography (silica gel,
n-hexane/AcOEt 50:1 to 3:1) to afford 2,4-di(ethoxycarbonyl)-3-
methylpyrrole 3a in 64% yield (72.1 mg).
Representative Procedure for the Phosphine-Catalyzed Reaction
Leading to the Formation of 2,3-Di-EWG-Substituted Pyrroles. To
a 1,4-dioxane solution (1 mL) of 1,3-bis(diphenylphosphino)propane
(dppp) (30.9 mg, 75 µmol) were added ethyl isocyanoacetate 1a (66
µL, 0.6 mmol) and ethyl butynoate 2a (58 µL, 0.5 mmol) under an Ar
atmosphere. The solution was stirred at 100 °C for 2 h. After the
consumption of 2a, the reaction mixture was cooled to room temperature
and filtered through a short Florisil pad and concentrated. The residue
was purified by column chromatography (silica gel, n-hexane/AcOEt
50:1 to 3:1) to afford 2,3-di(ethoxycarbonyl)-4-methylpyrrole 4a in 60%
yield (67.1 mg).
Conclusion
We have developed new synthetic procedures for the regio-
controlled formation of pyrroles via a formal [3 + 2] cycload-
dition of isocyanides 1 and electron-deficient alkynes 2. The
present heteroaromatization proceeds smoothly under either a
copper or a phosphine catalyst, and the two distinct regioiso-
meric pyrroles can be obtained selectively by merely choosing
the catalyst conditions. The reaction under a catalytic amount
of Cu2O and phen gives 2,4-di-EWG-substituted pyrroles,
whereas the reaction under dppp catalyst affords 2,3-di-EWG-
substituted pyrroles selectively. This interesting switching of
the regioselectivity is due to umpolung of the reactivity of the
alkynes 2, depending on the catalyst conditions. As mentioned
in Scheme 4, the nucleophilic isocyanide A generated by a C-H
activation with Cu2O undergoes the ordinary 1,4-addition to 2
leading to 3, whereas the 1,4-adduct of PR3 to 2 makes the
R-carbon attached to EWG electrophilic (E in Scheme 5) and
thereby the carbanion of 1 attacks the R-position of E leading
to 4.
Acknowledgment. We are grateful to the members in the
Research and Analytical Center for Giant Molecules at the
Graduate School of Science, Tohoku University for measure-
ment of NMR spectra and mass spectra and elemental analysis.
Experimental Section
Supporting Information Available: Analytical data for the
2,4-di-EWG-substituted pyrroles 3 and 2,3-di-EWG-substituted
pyrroles 4 (PDF). This material is available free of charge via
the Internet at http://pubs.acs.org.
Representative Procedure for the Copper-Catalyzed Reaction
Leading to the Formation of 2,4-Di-EWG-Substituted Pyrroles. To
a 1,4-dioxane solution (1 mL) of Cu2O (3.6 mg, 25 µmol) and 1,10-
phenanthroline (9.0 mg, 50 µmol) were added ethyl butynoate 2a (70
µL, 0.6 mmol) and ethyl isocyanoacetate 1a (55 µL, 0.5 mmol) under
JA051875M
9
9266 J. AM. CHEM. SOC. VOL. 127, NO. 25, 2005